title: Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene.
abstract: Accumulating evidence suggests that heterozygous mutations in the SQSTM1 gene, which encodes p62 protein, are associated with amyotrophic lateral sclerosis (ALS). Here, we report a Japanese patient with sporadic, late-onset ALS who harbored compound heterozygous SQSTM1 mutations (p.[Val90Met];[Val153Ile]). Autopsy examination revealed that although TDP-43 pathology was rather widespread, the selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in the lower motor neurons (LMNs) was a characteristic feature. No Bunina bodies were found. Ultrastructurally, p62-positive cytoplasmic inclusions observed in the spinal anterior horn cells were composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures. Another feature of interest was concomitant Lewy body pathology. The occurrence of distinct p62 pathology in the LMNs in this patient indicates the pathogenic role of SQSTM1 mutations in the development of a subset of ALS.
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.forename: Keiko
authors.initials: K
authors.lastname: Arakawa
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shimohata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein